{PDOC52044}
{PS52044; VLRF1}
{BEGIN}
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* Vms1-like release factor 1 (VLRF1) domain profile *
*****************************************************

Stalling of  ribosomes  engaged  in  protein synthesis can lead to significant
defects in  the  function  of  newly  synthesized  proteins and thereby impair
protein homeostasis.  Ribosomal  surveillance pathways scan for ribosomes that
are transiently  paused  or terminally stalled owing to structural elements in
mRNAs or  nascent  chain  sequences. Ribosome-associated quality control (RQC)
provides a  rescue  pathway  for  eukaryotic  cells to process faulty proteins
after translational  stalling of cytoplasmic ribosomes. The general mechanisms
and factors  acting  at  different  stages  of  RQC, from recognizing aberrant
translation to  degradation,  have  been  shown  to  be  highly  conserved  in
eukaryotes. Stalled  ribosomes are recognized by specific factors that trigger
the separation of large ribosomal subunits (LSUs) and small ribosomal subunits
(SSUs). Ribosome  splitting  recycles  the SSU, but the LSU remains associated
with a  tRNA  attached  to  an incomplete nascent polypeptide chain. Such LSU-
nascent chain  complexes  undergo processing by an addition of Ala (in mammals
and bacteria)  or Ala/Thr (in yeast) C-terminal tails ("CAT tails") to nascent
peptides. Tailing  serves  as a signal for the recruitment of specific factors
that mark  the  nascent  chains  by ubiquitination for subsequent degradation.
However, to  be  degraded,  nascent  chains first have to be released from the
tRNA. In  eukaryotes, this is accomplished by a specific nuclease that cleaves
off the  peptidyl-tRNA  CCA  end.  An  endonuclease,  the  ankyrin repeat (see
<PDOC50088>) and  zinc  finger  (see  <PDOC00028>) domain-containing protein 1
(ANKZF1; S.  cerevisiae  Vms1), selectively cleaves off the 3'-CCA nucleotides
of the  peptidyl-tRNA  on LSU RQC complexes and is responsible for the release
of the  ubiquitinated polypeptide from the tRNA in the LSU. Because the 3'-CCA
is invariant  on  all  tRNAs,  ANKZF1/Vms1 can act on ribosomes stalled at any
codon and   generate   a   CCA-less   tRNA   intermediate   incompatible  with
aminoacylation [1,2,3,4,5].

The ANKZF1/Vms1  Vms1-like  release  factor  1 (VLRF1) domain, which acts as a
peptidyl-tRNA hydrolase,  has  a catalytic loop bearing a conserved glutamine.
In addition  to  the  glutamine  in  the  active  site,  the VLRF1 domain also
contains conserved  vicinal arginines in the alpha-helix immediately following
the active-site loop. The cleavage mechanism involves remodelling and cleavage
of the  ribose-phosphate  backbone of the tRNA by a tyrosine and the GSQ motif
(see <PDB:5WHG>) [2,3].

The profile we developed covers the entire VLRF1 domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: May 2024 / First entry.

[ 1] Inada T., Beckmann R.
     "Mechanisms of Translation-coupled Quality Control."
     J. Mol. Biol. 436:168496-168496(2024).
     PubMed=38365086; DOI=10.1016/j.jmb.2024.168496
[ 2] Verma R., Reichermeier K.M., Burroughs A.M., Oania R.S., Reitsma J.M.,
     Aravind L., Deshaies R.J.
     "Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from
     stalled  ribosomes."
     Nature 557:446-451(2018).
     PubMed=29632312; DOI=10.1038/s41586-018-0022-5
[ 3] Su T., Izawa T., Thoms M., Yamashita Y., Cheng J., Berninghausen O.,
     Hartl F.U., Inada T., Neupert W., Beckmann R.
     "Structure and function of Vms1 and Arb1 in RQC and mitochondrial
     proteome  homeostasis."
     Nature 570:538-542(2019).
     PubMed=31189955; DOI=10.1038/s41586-019-1307-z
[ 4] Rodnina M.V.
     "Peptidyl-tRNA hydrolase as a key player in the liberation of
     truncated nascent  chains from the ribosomal subunit."
     Mol. Cell. 84:614-615(2024).
     PubMed=38364778; DOI=10.1016/j.molcel.2024.01.017
[ 5] Yip M.C.J., Shao S.
     "Detecting and Rescuing Stalled Ribosomes."
     Trends. Biochem. Sci. 46:731-743(2021).
     PubMed=33966939; DOI=10.1016/j.tibs.2021.03.008

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